This study will test the central hypothesis that our patented, minimally erythropoietic, form of erythropoietin (EPO), EPO-R76E, protects retinal ganglion cells (RGCs) from glaucoma pathogenesis by directly activating the Nrf2 pathway in these cells. Oxidative stress is known to contribute significantly to glaucoma pathogenesis. EPO can decrease oxidative stress through activation of Nrf2 signaling to result in increased expression of antioxidant proteins from the antioxidant response element (ARE). We will test our hypothesis through the following Specific Aims: 1) Determine how EPO-R76E influences the Nrf2 signaling pathway; 2) Compare EPO-R76E-induced Nrf2 pathway activation in RGCs, astrocytes, and Mller cells; and 3) Measure EPO-R76E induced signaling and the efficacy of EPO-R76E microparticles in a non-human primate model of glaucoma. We will use the microbead occlusion model of glaucoma in both species. We will utilize genetic and pharmacological approaches to determine the pathways activated and the relative contributions of astrocytes, Mller cells, and RGCs in EPO-R76E induced Nrf2/ARE activation. We will use cell-type specific recombinant adeno-associated viruses and promoters, pathway inhibitors, flow cytometry, and microscopy. Finally, we will test the efficacy of inherently-antioxidant microparticle loaded with EPO-R76E in a clinically relevant species, the squirrel monkey. We expect to gain greater insight into glaucoma pathogenesis leading to the identification of druggable targets. Further, we expect to demonstrate that EPO- R76E microparticles are a safe and effective IOP-independent treatment for glaucoma.!